New Way Found To See Light Through Novel Protein Identified By Dartmouth Geneticists

July 8, 2002 -- Dartmouth
Medical School geneticists have discovered a new class of proteins that
see light, revealing a previously unknown system for how light works.

The novel photoreceptors are part of the gears that drive biological
clocks, the cellular timekeepers of the circadian rhythm, which paces
life's daily ebb and flow in a 24-hour light-dark cycle. Their
identification also opens a window for genetically engineered drug
delivery systems that exploit the properties of these newfound
molecules.

The findings, by Drs. Jay Dunlap and Jennifer Loros, and graduate
student Allan Froehlich, will be published in an upcoming issue of
Science; they are currently reported online in Science Express.

Dunlap, professor and chair of genetics, and Loros, professor of
biochemistry, were the first to delineate circadian clockwork in
Neurospora, the common bread mold and one of the best-known genetic
model systems. They pieced together how the circadian cycle works and
demonstrated how light resets it through a complex of interwoven
molecular messages.

"That left open the question then of what actually absorbed the light.
What we found is a new paradigm within clocks," Dunlap says. "Light is
absorbed by a molecule that is actually within the clock and is an
activating element in the clock cycle. This is a new molecular
mechanism to see light and a new way for light to have an effect.
Although the protein has been known for sometime, this is a
configuration of activities that's not been reported before for any
protein."

Since bread mold belongs to the fungal phylogenetic kingdom, eventually
researchers may be able to harness the proteins against fungal disease.
"Virtually nothing is known about how pathogenic fungi respond to light
or whether that can be exploited for a noninvasive therapy," Dunlap
acknowledges. It may be a long shot, but drug therapies start with
properties people don't have. "If you want to do therapy--antifungal,
antibacterial or anything--you start looking for biochemical activities
that the host does not have that can be targeted on the pathogen."

Froelich, a graduate student with Dunlap and Loros, built on their
discovery that the gene frequency (frq) encodes a central cog of the
clock cycle and that light resets the clock by acting on frq. He
identified the frq parts necessary and sufficient for light induced
expression of the gene, and determined that the proteins that bind to
these parts are the clock proteins White Collar-1 and White Collar-2
(WC-1 and WC-2). He then showed that both proteins were sufficient for
binding, that under appropriate biochemical conditions they could also
detect light and, subsequently, that WC-1 is actually the photoreceptor
protein.

WC-1 is a transcription factor that partners with WC-2, and binds to
DNA of light-regulated genes. Transcription factors are proteins whose
role is to regulate expression of genes; they bind to DNA and turn on
genes, Dunlap explains. "This is the first case of a transcription
factor that is itself a photo pigment and a transcription factor that
contains both ability to turn on gene expression and ability to do that
in response to light within the same protein."